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J. Biol. Chem., Vol. 275, Issue 40, 31099-31106, October 6, 2000
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From the Molecular Biology and Virology Laboratory, The Salk
Institute for Biological Studies,
La Jolla, California 92037
The binding of atrial natriuretic peptide and
C-type natriuretic peptide (CNP) to the guanylyl cyclase-linked
natriuretic peptide receptors A and B (NPR-A and -B), respectively,
stimulates increases in intracellular cGMP concentrations. The
vasoactive peptides vasopressin, angiotensin II, and endothelin
inhibit natriuretic peptide-dependent cGMP elevations
by activating protein kinase C (PKC). Recently, we identified six
in vivo phosphorylation sites for NPR-A and five sites for
NPR-B and demonstrated that the phosphorylation of these sites is
required for ligand-dependent receptor activation. Here, we
show that phorbol 12-myristate 13-acetate, a direct activator of
PKC, causes the dephosphorylation and desensitization of NPR-B. In
contrast to the CNP-dependent desensitization process,
which results in coordinate dephosphorylation of all five sites in the receptor, phorbol 12-myristate 13-acetate treatment causes the dephosphorylation of only one site, which we have identified as Ser523. The conversion of this residue to alanine or
glutamate did not reduce the amount of mature receptor protein as
indicated by detergent-dependent guanylyl cyclase
activities or Western blot analysis but completely blocked the ability
of PKC to induce the dephosphorylation and desensitization of NPR-B.
Thus, in contrast to previous reports suggesting that PKC directly
phosphorylates and inhibits guanylyl cyclase-linked natriuretic peptide
receptors, we show that PKC-dependent dephosphorylation of
NPR-B at Ser523 provides a possible molecular explanation
for how pressor hormones inhibit CNP signaling.
Activation of Protein Kinase C Stimulates the
Dephosphorylation of Natriuretic Peptide Receptor-B at a Single Serine
Residue
A POSSIBLE MECHANISM OF HETEROLOGOUS DESENSITIZATION*
and
*
This work was supported by United States Public Health
Service Grants CA14195 and CA39780 (to T. H.).The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
Supported by National Research Service Award CA-67452 from the
National Cancer Institute. To whom correspondence should be addressed.
Dept. of Biochemistry, Molecular Biology and Biophysics, University of
Minnesota-Twin Cities, 356 Gortner Laboratory, 1479 Gortner Ave., St.
Paul, MN 55108. Tel.: 612-624-7251; Fax: 612-624-7282; E-mail:
Potter@tc.umn.edu.
§
Frank and Else Schilling American Cancer Society Research Professor.
Copyright © 2000 by The American Society for Biochemistry and Molecular Biology, Inc.
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